Process for the preparation of nicotinamide derivatives

Abstract

The present invention relates to a process for the preparation of nicotinamide derivatives of formula I, wherein R 1 to R 7 are as defined above and to pharmaceutically acceptable salts thereof. The compounds of formula I are useful for the treatment and/or prophylaxis of diseases which are associated with the modulation of cannabinoid 1 receptors (CB1 receptors) as described in the PCT Publ. WO 2006/106054.

1 . A process for the preparation of a nicotinamide derivative of formula I, 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of lower hydroxyalkyl, cycloalkyl which is unsubstituted or substituted by hydroxy or lower hydroxyalkyl, and —CH 2 —CR 8 R 9 -cycloalkyl; 
         R 8  is hydrogen or lower alkyl; 
         R 9  is selected from the group consisting of hydrogen, hydroxy and lower alkoxy; 
         R 2  is hydrogen; 
         or R 1  and R 2  together with the nitrogen atom they are attached to form a piperidinyl ring or a morpholinyl ring; 
         R 3  and R 7  are hydrogen or halogen; and 
         R 4 , R 5  and R 6  independently from each other are selected from the group consisting of hydrogen, lower alkyl, lower halogenalkyl, lower halogenalkoxy, cyano and halogen 
         and pharmaceutically acceptable salts thereof comprising the step of: a) coupling a 5,6-dihalogenated nicotinic acid derivative of formula III, 
       
       
         
           
           
               
               
           
         
         wherein X and Y stand for a halogen atom and R 10  is hydrogen or lower alkyl, 
         with an aryl metal species of formula IV, 
       
       
         
           
           
               
               
           
         
         wherein R 3  to R 7  are as defined herein before and M means boronic acid or a boronic acid ester, in the presence of a Pd catalyst under basic conditions to form a 5-aryl substituted nicotinic acid derivative of formula V, 
       
       
         
           
           
               
               
           
         
         wherein Y, R 3 , R 4 , R 5 , R 6 , R 7  and R 10  are as defined herein before. 
       
     
     
         2 . A process according to  claim 1 , wherein R 3 , R 4  and R 7  are hydrogen and R 5  and R 6  are halogen. 
     
     
         3 . A process according to  claim 2 , wherein R 3 , R 4  and R 7  are hydrogen and R 5  and R 6  are chlorine. 
     
     
         4 . A process according to  claim 1 , wherein the Pd catalyst is selected from the group consisting of complexes of palladium(II)acetate/triphenylphosphine mixtures, palladium(II)chloride-dppf (1,1′-bis(diphenylphosphino)ferrocene) and palladium(II)chloride bis(triphenylphosphino). 
     
     
         5 . A process according to  claim 1 , wherein the basic conditions for the coupling are achieved with the presence of a base selected from a tertiary amine and an alkali carbonate. 
     
     
         6 . A process according to a  claim 1 , wherein the coupling is performed in the presence of an organic solvent at a reaction temperature of 20° C. to 110° C. 
     
     
         7 . A process according to  claim 1  further comprising the steps of:
 b) hydrolyzing a 5-aryl substituted nicotinic acid derivative of formula V wherein R 10  is lower alkyl with a base to form a 5-aryl substituted nicotinic acid derivative of formula VI, 
 
       
         
           
           
               
               
           
         
         wherein Y, R 3 , R 4 , R 5 , R 6  and R 7  are as defined herein before; 
         c) introducing a trifluoroethoxy group into the 5-aryl substituted nicotinic acid derivative of formula VI to form a 6-trifluoroethoxy substituted nicotinic acid derivative of formula VII, 
       
       
         
           
           
               
               
           
         
         wherein 
         R 3 , R 4 , R 5 , R 6  and R 7  are as defined herein before; 
         and 
         d) forming the nicotinamide derivative of formula I by reacting the 6-trifluoroethoxy substituted nicotinic acid derivative of formula VII with an amine of formula VIII,
   R 1 R 2 NH  VIII,
 
 
         wherein 
         R 1  and R 2  are as defined herein before. 
       
     
     
         8 . A process according to  claim 7 , wherein the hydrolysis in step b) is performed with an alkali hydroxide. 
     
     
         9 . A process according to  claim 7 , wherein the 5-aryl substituted nicotinic acid derivative of formula V obtained from step a) is not isolated and is in situ subjected to the hydrolysis in step b) for the formation of the 5-aryl substituted nicotinic acid derivative of formula VI. 
     
     
         10 . A process according to  claim 7 , wherein the introduction of the trifluoroethoxy group in step c) is effected with 2,2,2-trifluoroethanol in the presence of a base and an organic solvent at a reaction temperature between 20° C. to 150° C. 
     
     
         11 . A process according to  claim 10 , wherein the base is selected from an inorganic base selected from an alkali hydroxide or from an organic base that is diazabicycloundecen or triazabicyclodecene. 
     
     
         12 . A process according to  claim 7 , wherein R 1  is cycloalkyl unsubstituted or substituted by hydroxy or lower hydroxyalkyl and R 2  is hydrogen. 
     
     
         13 . A process according to  claim 12 , wherein R 1  is 2-hydroxy cyclohexyl and R 2  is hydrogen. 
     
     
         14 . A process according to  claim 12 , wherein the amide formation is effected in the presence of a coupling agent and an organic solvent at a reaction temperature of 0° C. to 120° C. 
     
     
         15 . A process according to  claim 14 , wherein the coupling agent is selected from the group consisting of oxalyl chloride, N,N′-carbonyl-diimidazole (CDI), N,N′-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU).